Creation of 3D Digital Anthropomorphic Phantoms which Model Actual Patient Non-rigid Body Motion as Determined from MRI and Position Tracking Studies of Volunteers

Background: Patient motion during emission imaging can create artifacts in the reconstructed emission distributions, which may mislead the diagnosis. For example, in myocardial-perfusion imaging, these artifacts can be mistaken for defects. Various software and hardware approaches have been developed to detect and compensate for motion. There are various ways of testing the effectiveness of motion correction methods applied in emission tomography, including the use of realistic digital anthropomorphic phantoms. Purpose: The purpose of this study was to create 3D digital anthropomorphic phantoms based on MRI data of volunteers undergoing a series of clinically relevant motions. These phantoms with combined position tracking were used to investigate both imaging-data-driven and motion tracking strategies to estimate and correct for patient motion. Methods: MRI scans were obtained of volunteers undergoing a series of clinically relevant movements. During the MRI, the motions were recorded by near-infra-red cameras tracking using external markers on the chest and abdomen. Individual-specific extended cardiac-torso (XCAT) phantoms were created fit to our volunteer MRI imaging data representing pre- and post-motion states. These XCAT phantoms were then used to generate activity and attenuation distributions. Monte Carlo methods will then be performed to simulate SPECT acquisitions, which will be used to evaluate various motion estimation and correction strategies. Results: Three volunteers were scanned in the MRI with concurrent external motion tracking. Each volunteer performed five separate motions including an axial slide, roll, shoulder twist, spine bend, and arm motion. These MRI scans were then manually digitalized into 3D anthropomorphic XCAT phantoms. Activity and attenuation distributions were created for each XCAT phantom, representing fifteen individual-specific motions. Conclusions: Our results will be combined with the external motion tracking data to determine if external motion tracking accurately reflects heart position in patients undergoing cardiac SPECT imaging. This data will also be used to evaluate other motion correction methods in the future

A synthetic biology approach to probing nucleosome symmetry

The repeating subunit of chromatin, the nucleosome, includes two copies of each of the four core histones, and several recent studies have reported that asymmetrically-modified nucleosomes occur at regulatory elements in vivo. To probe the mechanisms by which histone modifications are read out, we designed an obligate pair of H3 heterodimers, termed H3X and H3Y, which we extensively validated genetically and biochemically. Comparing the effects of asymmetric histone tail point mutants with those of symmetric double mutants revealed that a single methylated H3K36 per nucleosome was sufficient to silence cryptic transcription in vivo. We also demonstrate the utility of this system for analysis of histone modification crosstalk, using mass spectrometry to separately identify modifications on each H3 molecule within asymmetric nucleosomes. The ability to generate asymmetric nucleosomes in vivo and in vitro provides a powerful and generalizable tool to probe the mechanisms by which H3 tails are read out by effector proteins in the cell

The association between preoperative spinal cord rotation and postoperative C5 nerve palsy

BACKGROUND: C5 nerve palsy is a known complication of cervical spine surgery. The development and etiology of this complication are not completely understood. The purpose of the present study was to determine whether rotation of the cervical spinal cord predicts the development of a C5 palsy. METHODS: We performed a retrospective review of prospectively collected spine registry data as well as magnetic resonance images. We reviewed the records for 176 patients with degenerative disorders of the cervical spine who underwent anterior cervical decompression or corpectomy within the C4 to C6 levels. Our measurements included area for the spinal cord, space available for the cord, and rotation of the cord with respect to the vertebral body. RESULTS: There was a 6.8% prevalence of postoperative C5 nerve palsy as defined by deltoid motor strength of /= 11 degrees ) and palsy (point-biserial correlation = 0.94; p \u3c 0.001). A diagnostic criterion of 6 degrees of rotation could identify patients who had a C5 palsy (sensitivity = 1.00 [95% confidence interval, 0.70 to 1.00], specificity = 0.97 [95% confidence interval, 0.93 to 0.99], positive predictive value = 0.71 [95% confidence interval, 0.44 to 0.89], negative predictive value = 1.00 [95% confidence interval, 0.97 to 1.00]). CONCLUSIONS: Our evidence suggests that spinal cord rotation is a strong and significant predictor of C5 palsy postoperatively. Patients can be classified into three types, with Type 1 representing mild rotation (0 degrees to 5 degrees ), Type 2 representing moderate rotation (6 degrees to 10 degrees ), and Type 3 representing severe rotation (\u3e/= 11 degrees ). The rate of C5 palsy was zero of 159 in the Type-1 group, eight of thirteen in the Type-2 group, and four of four in the Type-3 group. This information may be valuable for surgeons and patients considering anterior surgery in the C4 to C6 levels

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Vertical transmission of Mycobacterium tuberculosis in KwaZulu Natal: impact of HIV-1 co-infection

BACKGROUND: Increases in perinatal TB have paralleled the exacerbation of the TB epidemic in KwaZulu Natal. The exact risks for vertical transfer of Mycobacterium tuberculosis (VTRTB) to the baby are unknown, as is the impact of HIV-1 co-infection, which frequently accompanies maternal TB disease in the region. DESIGN: Prospective case series study of 82 HIV-1-infected and 25 non-infected pregnant mothers, King Edward VIII Hospital, KwaZulu Natal, South Africa. RESULTS: Perinatal mortality in HIV-1/TB diseased mothers was 85/1000 and associated with maternal anaemia (P = 0.02); 46% of newborns were premature, 66% low birth weight and 49% intrauterine growth restricted. These were significantly higher than overall hospital rates (P \u3c 0.01, OR 4.8, 95%CI 3.2-7.0). Sites of detection of maternal TB, distribution of bacteriologically-proven TB, obstetric comorbidity and perinatal morbidity were similar in HIV-1-infected and non-infected mothers. VTRTB was detected in 16 newborns (16%), occurring similarly in bacteriologically-proven and suspected maternal TB disease, with no difference between HIV-1-infected and non-infected mothers. Eleven newborns with VTRTB were HIV-1 exposed; 64% acquired HIV-1 and died from rapidly progressive disease by 10 months of age. HIV-1-infected mothers and their exposed newborns had significantly lower CD4 counts. No association between perinatal maternal viral load, CD4 count or VTRTB was detected. CONCLUSION: Mothers with TB disease in pregnancy are at risk for significant perinatal morbidity, mortality and VTRTB

Digital anthropomorphic phantoms of non-rigid human respiratory and voluntary body motion for investigating motion correction in emission imaging

The development of methods for correcting patient motion in emission tomography has been receiving increased attention. Often the performance of these methods is evaluated through simulations using digital anthropomorphic phantoms, such as the commonly used extended cardiac torso (XCAT) phantom, which models both respiratory and cardiac motion based on human studies. However, non-rigid body motion, which is frequently seen in clinical studies, is not present in the standard XCAT phantom. In addition, respiratory motion in the standard phantom is limited to a single generic trend. In this work, to obtain a more realistic representation of motion, we developed a series of individual-specific XCAT phantoms, modeling non-rigid respiratory and non-rigid body motions derived from the magnetic resonance imaging (MRI) acquisitions of volunteers. Acquisitions were performed in the sagittal orientation using the Navigator methodology. Baseline (no motion) acquisitions at end-expiration were obtained at the beginning of each imaging session for each volunteer. For the body motion studies, MRI was again acquired only at end-expiration for five body motion poses (shoulder stretch, shoulder twist, lateral bend, side roll, and axial slide). For the respiratory motion studies, an MRI was acquired during free/regular breathing. The magnetic resonance slices were then retrospectively sorted into 14 amplitude-binned respiratory states, end-expiration, end-inspiration, six intermediary states during inspiration, and six during expiration using the recorded Navigator signal. XCAT phantoms were then generated based on these MRI data by interactive alignment of the organ contours of the XCAT with the MRI slices using a graphical user interface. Thus far we have created five body motion and five respiratory motion XCAT phantoms from the MRI acquisitions of six healthy volunteers (three males and three females). Non-rigid motion exhibited by the volunteers was reflected in both respiratory and body motion phantoms with a varying extent and character for each individual. In addition to these phantoms, we recorded the position of markers placed on the chest of the volunteers for the body motion studies, which could be used as external motion measurement. Using these phantoms and external motion data, investigators will be able to test their motion correction approaches for realistic motion obtained from different individuals. The non-uniform rational B-spline data and the parameter files for these phantoms are freely available for downloading and can be used with the XCAT license